This Mentored Research Scientist Development Award (K01) proposes to investigate the neurophysiological consequences of methamphetamine self-administration while providing the candidate (Dr. Michael Beckstead) with training in behavioral neuroscience. Dr. Beckstead's immediate goals include learning behavioral techniques including stereotaxic surgeries, brain site-specific injections, methamphetamine self administration procedures, and experimental design and interpretation of models of psychostimulant administration. In addition to the scientific aims of the studies presented, the ultimate goal of the proposal is to train the investigator with behavioral techniques that, along with established expertise in electrophysiology, will form the basis for a career as an independent investigator. The career development plan involves mentorship in behavioral techniques from an established behavioral neuroscientist (Dr. Gregory Mark) while utilizing the resources and expertise of one of the top behavioral departments in the country. The experimental procedures will investigate the hypothesized relationship between methamphetamine self-administration, intracellular calcium levels, and dendrodendritic dopamine transmission in the ventral tegmental area of mice. Methamphetamine induces synaptic plasticity and D2 dopamine autoreceptor subsensitivity, but the mechanisms involved are poorly understood. Furthermore, no study has investigated the role of synaptic plasticity on methamphetamine self-administration. Using recently discovered tools including a synaptic potential mediated by dopamine and a novel form of plasticity at dopamine synapses, the experiments will determine if dopamine plasticity plays a role in methamphetamine self-administration. Relevance: Determining the neurophysiological consequences of methamphetamine self-administration is the first step in identifying intervention strategies to prevent and treat human drug abuse. A better understanding of the neural adaptations associated with drug use and administration may help to explain why some methamphetamine users become addicted to the drug, and may lead to treatments to help patients break the difficult cycle of addiction.